Summary: fMRI Network Analysis and Resting State Studies a. Resting state Connectivity and alcohol use disorder domains We have been in the process of analyzing major networks such as Salience, Default Mode, and Executive Control networks and their relationship with the circuits involved in addiction cycle as defined by Koob et al (2010). Currently we have collected and are processing the resting state data of healthy control volunteers and alcohol dependent patients. Preliminary results indicate that alcohol dependent individuals have less within network connectivity in the Default Mode Network, when compared to healthy controls. Furthermore, we have identified differences in spectra between groups for these same networks. b. Resting State Connectivity and Genetic Variants In collaborations with various NIAAA sections, we are currently investigating the modulatory effects of several genes on resting state connectivity of alcohol dependent patients in comparison to non-dependent controls. Amongst these genes are: CD38 The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism. In collaboration with Dr. Mary Lee (Dr. Leggios CPN) we have analyzed seed-based resting state functional connectivity in healthy control individuals with the minor and major allele of the CD38 gene rs3796863. Individuals with the minor allele showed increased functional connectivity between the left ventral striatum and the anterior cingulate cortex compared to individuals with the major allele. These results have been combined with other imaging (PET) and non-imaging behavioral data to investigate this genes effect on reward processing in healthy individuals. The manuscript for this study: A role for the CD38 rs3796863 polymorphism in alcohol and monetary reward: possible involvement of dopamine signaling has been submitted to Biological Psychiatry for publication. DAT - Altered dopaminergic signaling pathways and heightened ventral striatum (VS) activation in response to reward in addiction has been related to functional polymorphisms of the dopamine system. Dopamine related post-synaptic activity depends on the presence of dopamine in the synapse, which in turn is related to the activity of the dopamine transporter (DAT). Expression of DAT is influenced by a polymorphism of the DAT gene. There is evidence that the 9-repeat is associated with decreased DAT levels. This could represent a possible neuroimaging endophenotype of higher VS-dopamine availability reflected as higher VS reactivity in individuals with the 9-repeat allele when compared to individuals with the 10-repeat allele. In collaboration with Dr. Lohoffs CGET, we are currently conducting resting state analyses to determine whether healthy controls and patients with alcohol use disorder with the 9-repeat allele had higher VS-connectivity compared to those with the 10-repeat allele. We are also investigating the effects of these variants on emotional processing of fear and and anger. CRHNA5 We have provided over a hundred resting data sets to Dr. Ramchandanis HP section to analyze the effects of CHRNA5 variants on the resting state of alcohol dependent and healthy control subjects. The nicotinic acetylcholine receptor (nAChR) has been shown to be associated with nicotine addiction, and potentially alcohol use disorders. Through a collaboration with Dr. Ramchandanis section, we will be assessing whether altered functional connectivity related to CHRNA5 mediates the risk for excessive alcohol use. c. Resting State Connectivity under acute alcohol administration Studies conducted by Dr. Lovinger's Laboratory for Integrative Neuroscience have demonstrated a selective acute ethanol effect on external globus palidus (GPe) neurons that have a specific connectivity with the dorsal striatum (Abrahao et al._2016). Based on this finding and the known role of the basal ganglia in habitual and compulsive behaviors seen in addiction, we investigated the functional resting-state connectivity changes of the GPe and basal ganglia of 25 healthy social drinkers before and after intravenous ethanol administration. Using a network based statistical analysis, our preliminary results show that after acute ethanol administration resting-state connectivity of the GPe with the caudate and putamen is significantly altered. We also found changes in the connectivity of the substantia nigra, subthalamic nucleus and GPi and other cortical regions. Further analysis of this data and its translational implications is underway.